Epiregulin expression by Ets-1 and ERK signaling pathway in Ki-ras-transformed cells.
Epiregulin belongs to the epidermal growth factor family, binds to the epidermal growth factor receptor, and its expression is upregulated in various cancer cells, but the regulatory mechanism is unclear. We investigated the regulatory mechanism of epiregulin expression in Ki-ras-transformed cancer cells. In 267B1/Ki-ras cells, the RAF/MEK/ERK pathway was constitutively activated, epiregulin was up-regulated, and the expression and phosphorylation of Ets-1 were augmented. The inhibition of ERK by PD98059 decreased epiregulin and Ets-1 expression and suppressed the growth of 267B1/Ki-ras cells. A chromatin immunoprecipitation assay demonstrated that Ets-1 was bound to human epiregulin promoter, and this binding was abolished by PD98059. Silencing of Ets-1 by RNA interference decreased cellular epiregulin transcript expression. We suggest that the Ki-ras mutation in 267B1 prostate cells constitutively activates the RAF/MEK/ERK pathway and induces the activation of the Ets-1 transcription factor, ultimately leading to the increased expression of epiregulin.
Cho
Min-Chul
MC
Department of Bioscience and Biotechnology, Konkuk University, 1 Hwayng-dong, Gwangjin-gu, Seoul 143-701, Republic of Korea.
Choi
Hee-Sook
HS
Lee
Sojung
S
Kim
Bo Yeon
BY
Jung
Mira
M
Park
Sue Nie
SN
Yoon
Do-Young
DY
D000818:Animals; D002461:Cell Line, Transformed; D045744:Cell Line, Tumor; D004815:Epidermal Growth Factor / Q000235:genetics*; D066260:Epiregulin; D048049:Extracellular Signal-Regulated MAP Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D005419:Flavonoids / Q000494:pharmacology; D005786:Gene Expression Regulation; D006801:Humans; D008297:Male; D051379:Mice; D011401:Promoter Regions, Genetic; D011467:Prostate / Q000378:metabolism; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D050784:Proto-Oncogene Protein c-ets-1 / Q000235:genetics / Q000378:metabolism*; D034622:RNA Interference; D015398:Signal Transduction; D018631:ras Proteins / Q000235:genetics
C587880:EREG protein, human; C494041:ETS1 protein, human; D066260:Epiregulin; C587881:Ereg protein, mouse; D005419:Flavonoids; D047428:Protein Kinase Inhibitors; D050784:Proto-Oncogene Protein c-ets-1; D004815:Epidermal Growth Factor; D048049:Extracellular Signal-Regulated MAP Kinases; D018631:ras Proteins; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one